The objective of our HL research program is to develop stereo- and enantiocontrolled methods for constructing complex guanidines and other strongly basic molecules. These structures are targeted because guanidine and amine functional group are found in a disproportionately high percentage of pharmacologically-active, natural products and existing drugs and drug candidates, and methods for their chemical synthesis are less developed than other organic synthesis tools. If the aims of this application are realized, biomedical researchers will have new tools for preparing and modifying the structure of complex organic molecules containing basic functional groups. In the long term, the availability of the new organic synthesis methods that we are developing will facilitate discovery and production of improved chemical agents for treating medical disorders Total synthesis investigations will be carried out in four structurally distinct areas: hetisine alkaloids, palau'amine and congeners, massadine and sarain A. In each case, no synthesis entries to these structurally intricate and novel molecules exist. These molecules are targeted in part because of their unusual biological properties. Alkaloids of the hetisine type possess antiarrhythmic properties and low toxicity;the hetisine alkaloid guan-fu base A is currently undergoing Phase III clinical trials in China. Palau'amine is a remarkably non-toxic immunosuppressive agent. Massadine is an inhibitor of geranyl geranyl transferase I of the pathogenic fungus Candida albicans, as geranyl geranyl transferase I of Candida albicans shares only 30% homology with the corresponding human enzyme, it represents a novel lead in the search for new antifungal agents. Our ongoing studies in the crambescidin and batzelladine alkaloid areas focus on identifying structurally simple congeners displaying promising anti-cancer and anti-HIV activities that could serve as practical lead compounds for drug development. The proposed investigations are founded on discoveries made during the current project period of new strategies for preparing complex alkaloids by cyclocondensation and cycloaddition reactions, and the utility of tethered bisguanidine analogs of batzelladine alkaloids to inhibit protein-protein interactions involving large surface contacts.